Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening

Abstract

Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.

Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation

“…Taken together, our data suggest the efficacy of Pitavastatin-NPs on post-infarct LV remodeling was predominantly mediated by its efficacy on inflammatory cells. Similar to the previous reports, 20,21,25) Pitavastatin-NPs showed its efficacy at a lower concentration as compared with an equivalent dose of pitavastatin solution.…”

“…In myocardium after ischemia-reperfusion, PLGA nanoparticles distribute in myocardial tissues exposed to ischemia. 20,25) After MI, howev- er, it is speculated that PLGA nanoparticles are hardly delivered to the infarcted myocardium due to disrupted blood flow. Actually, there were no apparent fluorescent signals emitted by FITC-NPs in the infarcted zone of the heart.…”

“…Flow cytometry: Cell isolation and flow cytometry were performed as previously described. 21,22,25) Peripheral blood was collected by cardiac puncture and EDTA (ethylene diamine tetra acetic acid) (Sigma Aldrich, St. Louis, MO) was added. The erythrocytes were then lysed with VersaLyse Lysing solution (BD Biosciences, San Jose, CA) for 10 minutes at room temperature.…”

“…20,25) The extracted heart was fixed with 10% neutral buffered formalin and then embedded in paraffin. Sections were cut at 7 μm thickness and stained with Masson's Trichrome solution.…”

A Mechanism Study Underlying the Protective Effects of Cyclosporine-A on Lung Ischemia-Reperfusion Injury

“…Previous study suggested that pharmacological inhibitor of Cyp-D, cyclosporine-A (CsA), can inhibit MPTP and protect cardiac cells against oxidative stress, hypoxia, and I/R [7,8]. CsA was previously considered as a calcineurin inhibitor that is widely used to prevent acute rejection after liver transplantation [9].…”